The natural articulating joint (diarthrodal joint) comprises adjacent bones having opposing hyaline cartilage surfaces held together by a fibrous collagenous capsule defining a joint space. The inner wall of this capsule is lined with synovial cells. Contained within the capsular joint space is an acellular synovial fluid. The function of the synovial fluid is to provide lubrication for the articulating surfaces.
In a healthy joint, cells within the articular cartilage produce an extracellular matrix (ECM) containing a high percentage of proteoglycans. These proteoglycans contain sulfated functional groups that retain water, thereby providing the cartilage with its lubricating qualities. These cells may also secrete small amounts of cytokines as well as matrix metalloproteinases (“MMPs”). These cytokines and MMPs help regulate the metabolism of the hyaline cartilage cells.
There appear to be many causes of degenerative joint disease (DJD). For example, gradual degeneration of the joint may be caused by wear, by trauma, by misalignment, by genetics, or by mechanical instabilities in other portions of the body. In many instances, gradual wear of the hyaline cartilage cause the cells therein (or invading macrophages) to emit larger than normal amounts of the above-mentioned cytokines. In other instances of DJD, genetic factors, such as programmed cell death, or apoptosis can also cause the cells within the hyaline cartilage to emit abnormally large amounts of these cytokines into the extracellular matrix of the hyaline cartilage and synovial fluid.
Although the progression of DJD (also called “osteoarthritis”, or “OA”) is largely dependent upon etiology, it is often the case that the high levels of the cytokines present in the hyaline cartilage begin to mediate the degradation of the extracellular matrix of the cartilage. Concurrently, enzymes in the synovial fluid both upregulate MMPs and downregulate MMP inhibitors. The MMPs (under mediation by the cytokines) begin cleaving the water-retaining portions of the proteoglycans, thereby reducing its water-retaining and lubricious qualities. This degradation leads to a less lubricious hyaline cartilage, thereby increasing the wear upon the hyaline cartilage. This degenerative cascade also often leads to inflammation of the synovial lining, which often produces a thickening and fibrillation of the synovium, and the creation of finger-like villae with the synovium. When the natural regeneration of these cartilage layers is slower than this degenerative process, these changes cause even more mechanical instability, thereby causing the hyaline cartilage cells, the synovium cells and the invading macrophages to emit even more cytokines, thereby typically upregulating MMPs.
In addition to the foregoing, posterior elements of the spine called the “facet joints” help to support axial, torsional and shear loads that act on the spinal column. Furthermore, the facet joints are diarthroidal joints that provide both sliding articulation and load transmission features. The facet's articular surfaces contact in extension, limiting rotation and increasing compressive load. The articular surfaces also contact on one side of the spine in lateral bending and axial rotation, also limiting rotation and transferring load. Early facet osteoarthrosis is relatively mild and is confined to the articular cartilage, capsule, and synovium, but eventually involves the subchondral bone and the margins equally on both sides of a motion segment. With advancing degeneration, the joint capsule undergoes significant changes including increasing fibrosis and vascularization, which has been reported to become hyperemic with infiltration of inflammatory cells, enlargement, and fibrosis.
The posterior zygo-apophyseal joints (facet joints) may be a significant source of spinal disorders and, in many cases, debilitating pain. The articular cartilaginous surfaces can degenerate due to mechanical or biological factors and cause pain as with other joint osteoarthritis. Synovial cysts of the facet joints occur most commonly in association with degenerative disease of the spine in older individuals. The association of these cysts with trauma, rheumatoid arthritis, spondylolysis and kissing spinous processes also has been reported. These cysts can cause symptoms and signs from direct compression of the dura. For example, a patient may suffer from arthritic facet joints, severe facet joint tropism or otherwise deformed facet joints, facet joint injuries, etc. There is currently a lack of suitable intervention procedures for facet joint disorders. Facet blocks with anesthetic and cortisone, facet denervation procedures, radiofrequency ablation of the nerve supply to the joint, or even spinal fusions have been recommended. In the early stages of degeneration, pain may be controlled by blocking the medial branch of the lumbar zygapophyseal (facet) joints (kryorhizotomy). However, this treatment mode of treatment is considered for temporary relief of pain. Facetectomy, or the removal of the facet joints, may provide some relief, but is also believed to significantly decrease the stiffness of the spinal column (i.e., hypermobility) in all planes of motion: flexion and extension, lateral bending, and rotation. Furthermore, problems with the facet joints can also complicate treatments associated with other portions of the spine. By way of example, contraindications for artificial discs include arthritic, deformed, unstable, or painful facet joints. Accordingly, there is a need for a facet joint treatment that addresses these concerns.
Accordingly, there is a need for a minimally invasive treatment of facet joints.
Braun, Expert Opin. Biol. Ther. 3(1):141-168 (2003) (“Braun I”) reviews the efficacy of infliximab, a high specificity antagonist of TNF-α, in treating chronic inflammatory diseases. Braun reports that infliximab is delivered through essentially systemic administration routes. Braun does not report any local administration routes.
Braun, Ann. Rheum. Dis., 61 (Supp. III):;iii51-iii60 (2002), reviews the international experience of the use of anti-TNF α therapy for ankylosing spondylitis. Braun II reports that anti-TNF-α drugs are delivered through essentially systemic administration routes. Braun II does not report any local administration routes.
Olmarker, Spine, 26(8):863-9 (2001) (“Olmarker I”) and Aoki, Spine, 27(15):1614-17 (2002) teach that TNF-α appears to play a role in the producing the pain associated with the nucleus pulposus contacting nerve roots of the spinal cord.
U.S. Published Patent Application No. US 2003/0039651 (“Olmarker II”) teaches a therapeutic treatment of nerve disorders comprising administration of a therapeutically effective dosage of at least two substances selected from the group consisting of TNF inhibitors (both specific and non-specific), IL-1 inhibitors, IL-6 inhibitors, IL-8 inhibitors, FAS inhibitors, FAS ligand inhibitors, and IFN-gamma inhibitors. In the examples of Olmarker II, it is taught that these substances are to be administered through systemic pathways. In particular, Olmarker II teaches that “the major contribution of TNF-alpha may be derived from recruited, aggregated and maybe even extravasated leukocytes, and that successful pharmacologic block may be achieved only by systemic treatment”.
U.S. Pat. No. 6,419,944 (“Tobinick I”) discloses treating herniated discs with cytokine antagonists, including infliximab. However, Tobinick teaches that local adminstration involves an extradiscal injection between the disc and spinal cord. Accordingly, Tobinick does not teach a procedure involving directly administering a specific cytokine antagonist (such as infliximab) into a capsuled space.
U.S. Published Patent Application No. 2003/0049256 (Tobinick II) discloses that injection of such therapeutic molecules to the anatomic area adjacent to the spine is accomplished by interspinous injection, and preferably is accomplished by injection through the skin in the anatomic area between two adjacent spinous processes of the vertebral column.
Tobinick II discloses several spine and orthopaedic applications: Spinal Cord Injury (#12); neuropathic pain (#14); lumbar and Cervical Radiculopathy (#15); low back pain (#17), and Vertebral Disc Disease (#19). Tobinick teaches a parenteral/perispinal route of administration for spinal cord injuries; a perispinal route of administration for neuropathic pain; a perispinal route of administration for lumbar and Cervical Radiculopathy; a parenteral/perispinal route of administration for low back pain; and a perispinal route of administration for Vertebral Disc Disease. In each of applications Nos. 14, 15, 17 and 19, Tobinick appears to teach that the disc must be herniated, torn or leaking and so an extruded nucleus pulposus is the target tissue.
Tobinick II further teaches that TNF antagonists may be administered by interspinous injection in the human and that the dosage level is in the range of 1 mg to 300 mg per dose, with dosage intervals as short as two days. Tobinick II further discloses that Interleukin-1 antagonists are administered in a therapeutically effective dose, which will generally be 10 mg to 200 mg per dose, and their dosage interval will be as frequent as once daily.
Tobinick, Swiss Med. Weekly, 133:170-77 (2003), (“Tobinick III”) teaches both perispinal and epidural administration of TNF inhibitors for spine related therapies.
Alini, Eur. Spine J., 11(Supp.2):S215-220 (2002), teaches therapies for early stage disc degeneration disease, DDD, including injection of inhibitors of proteolytic enzymes or biological factors that stimulate cell metabolic activity (i.e., growth factors) in order to slow down the degenerative process. Alini I does not teach any similar injections into joints having synovial fluid.
U.S. Published Patent Application US2002/0026244 (“Trieu”) discloses an intervertebral disc nucleus comprising a hydrogel that may deliver desired pharmacological agents. Trieu teaches that these pharmacological agents may include growth factors such as TGF-B and anti-inflammatory drugs, including steroids. Trieu further teaches that these pharmacological agents may be dispersed within the hydrogel having an appropriate level of porosity to release the pharmacological agent at a desired rate. Trieu teaches that these agents may be released upon cyclic loading or upon resorption. Trieu does not teach any similar injections into joints having synovial fluid.
Maeda et al. Spine, 25(20):166-169 (2000), reports on the in vitro response to interleukin-1 receptor antagonist protein (IRAP) of rabbit annulus fibrosus exposed to IL-1. Maeda suggests that IRAP could be useful in inhibiting the degradation of the disc. Maeda does not teach any similar utility for joints having synovial fluid.
Igarashi et al., ISSLS Abstract #262 (May 13-17, 2003), sought to quantify the levels of various cytokines present within the facet joints of patients suffering from low back pain and sciatica. Igarashi appears to report that the levels of TNF-α were below the detection limits of the assay, but that the higher levels of IL-1β (for the patients with lumbar canal stenosis), and IL-6 were each statistically significant.
EP 1153607 A2 (“Dunn”) discloses injecting anti-cytokines (and in particular, an anti-TNF antibody called “Enbrel™”, which binds only soluble TNF), anti-kinases, anti-proteases, and anti-growth factors into orthopaedic joints, including those of the vertebrae. Dunn also discloses that these agents may be administered with a lubricant, such as hyaluronic acid.
U.S. Pat. No. 5,095,037 (“Iwamitsu”) discloses local administration of a composition comprising (a) an effective amount of hyaluronic acid or its salt, and (b) an effective amount of an anti-inflammatory agent. Iwamitsu particularly discloses Diclofenac, a COX-2 enzyme inhibitor, as one suitable anti-inflammatory agent.
WO 03/000190 A2 (“Thompson”) discloses a composition comprising glycosaminoglycans encapsulated in a liposomal delivery system for intra-articular administration for the treatment of osteoarthritis. Thompson further teaches that the composition may further include additional benefit agents such as p38 kinase inhibitors, TNF inhibitors, and inhibitors of enzymes that are involved in the destruction of articulating joints and synovial fluid components (such as hyaluronidase inhibitors, MMP inhibitors, aggrecanse inhibitors, or apoptosis inhibitors such as EPO), and cartilage enhancing factors such as TGF-β and BMP. Thompson does not specifically teach p38 kinase inhibitors having high specificity towards p38 kinase.
Certain molecules, such as tetravalent guanylhydrazone, non-specifically inhibit p38 kinase.
Wittenberg et al., Arthritis Rheum., 36(10):1444-50 (October 1993) investigated the major source of eicosanoid release in arthritic joint tissues. Release of prostaglandin E2 (PGE2), 6-keto-PGF1 alpha, leukotriene B4 (LTB4), and LTC4 were measured. Wittenberg reported in vitro experiments showing that the PG release was significantly inhibited by the addition of indomethacin or diclofenac (a COX-2 enzyme inhibitor) at either 10−5 moles/liter or 10−7 moles/liter. Wittenberg concluded that synovial tissue appears to be the major source of eicosanoids in synovial fluid, and that indomethacin and diclofenac inhibit the release of PG, but not LT, from various joint tissues.